Children exposed to Lead (Pb) show memory deficits associated with low levels of intelligence whereas, children and adults are equally sensitive to Methyl Mercury (CH3Hg). The biochemical basis of cognition has been shown to be dependent on proper functioning of two key enzymes in the hippocampus and the cerebellum namely the protein Kinase C (PKC) and Nitric Oxide Synthase (NOS). These enzymes are known to have multiple isoforms which are modulated by a number of endogenous and exogenous second messengers, neurotransmitters etc. The long term of our research is to delineate the role of PKC-NOS-NMDA complex to understand the mechanism of Pb and CH3HG induced neurotoxicity. The hypothesis to be tested in this proposal is that Pb and CH3Hg mediated developmental neurotoxicity. The hypothesis to be tested in this proposal is that Pb and CH3Hg mediated developmental neurotoxicity is dependent on single or multiple isoforms of PKC and NOS, and the regulation of glutamatergic neurotransmiss ion. The specific aims are: a) environmentally relevant Pb or CH3Hg exposure during the brain development results in changes of PKC and NOS and changes are isoform specific; b) The isoform specifics changes of PKC and NOS by perinatal and changes are isoform specific; b) The isoform specific changes of PKC and NOS by perinatal exposure of Pb and CH3Hg modulate the neurotransmitter pathways critical to cognitive functions; c) the changes in PKC and NOS isoforms, and NMDA receptors are related to the blood and tissue levels of Pb and Hg. The developing brains from rats of Post Natal Day (PND) 5,7, 10, 15, 21, 30, 45, 60 exposed to 1% Pb or 0.01% CH3Hg in deionized distilled drinking beginning at conception through 21 days after limiting will be used. We will study Pb and CH3Hg effects on: a) alpha-PKC, epsilon-PKC and zeta-PKC, b) nNOS, iNOS, and eNOS; c) NMDA specific glutamate receptor, and d) correlate results from these studies with the levels of Pb and CH3Hg in the tissue and blood. At the completion of this project we expect to have provided new information on the mechanism of Pb and CH3Hg neurotoxicity. Furthermore we will have detailed the sensitivity of different isoforms of PKC and NOS to Pb and CH3Hg insult and their influence on the NMDA receptors. All research activities will be appropriately evaluated. A corollary influence of this research will be that Alcorn State University will gain a strong biomedical research base.